?DESCRIPTION (provided by applicant): Overall In four scientific projects and four cores, we propose to study A PrP, and tau prions causing neurodegeneration. The discovery that prions cause Alzheimer's disease and other neurodegenerative diseases including frontotemporal dementias, Parkinson's disease, and ALS opens new research strategies for deciphering the pathogenesis of these illnesses and developing novel therapeutic approaches. Fundamental to understanding all prions is defining the structural transition that a particular protein undergoes when it becomes a prion. In this P01 renewal application, we plan to exploit new data published by us and others contending that A and tau, like PrP, can acquire conformations that are self-propagating; thus, they are prions. In each case, these alternative conformations are enriched for -sheet structure and readily polymerize in amyloid fibrils that often condense into plaques r tangles. In Project 1, we propose to study the properties of strains of A prions using bigenic mice that we created, to develop cultured cell bioassays that can detect A and tau prions, to investigate human (Hu) PrP prions using bigenic mice expressing bank vole (BV) PrP or chimeric Hu/BVPrP transgenes, and to determine if cultured cells expressing BVPrP can support the replication of human prion strains. In Project 2, we propose to continue structural studies of PrPSc formed from recombinant PrP utilizing an 89-mer fragment that initiated replication of anchorless PrPSc prions, to continue structural studies of A with emphasis on naturally occurring mutants, and to initiate structural studies of tau prions. In Project 3, we propose to determine the structure of A prions by solution and solid-state NMR; to monitor A assembly using multiple probes that are sensitive to both global and local conformations; to create thioamide- containing peptides and foldamers that enhance or inhibit individual steps of amyloid initiation, elongation, and fragmentation; and to synthesize a series of crosslinking reagents to probe the distribution of distances between Lys and Arg residues in A, PrP and tau prions. In Project 4, we propose to adapt and apply integrative structural modeling to protein self-assembly, thus facilitating simultaneous modeling of multiple structural states based on sparse, noisy, ambiguous and incoherent data of different kinds.